An emerging concept is that the complex microbial communities that comprise periodontal consortia consist of both beneficial and pathogenic species. The implication is that periodontal disease can be treated by selectively eliminating putative pathogens, while minimizing the destruction of the commensal members of the community. We propose to engineer a family of nanoplatforms to target photosensitizers (PS) and PS/drug or antimicrobial peptide pairs to periodontal pathogens. We will test the hypothesis that the selective killing of targeted PS can be significantly enhanced by appropriate PS/drug or PS/antimicrobial peptide combinations. We will engineer nanoplatforms known as protein cages to implement our design strategy. In preliminary studies we have developed methods to target and kill biofilm-forming pathogens with protein cages functionalized with a photosensitizer (PS). In parallel, we developed a method for triggered release of a drug coupled to a protein cage. We will build upon this expertise to fabricate multifunctional nanoplatforms for targeted combinatorial therapy. The ability of our engineered nanoplatforms to selectively kill periodontal pathogens will be characterized in planktonic and established biofilm in vitro systems. We will determine which combinations of PS and enhancer are most effective in producing additive or synergistic killing of pathogens while maintaining selectivity. The specific aims (SA) are organized in terms of three combinations of treatment modalities: SA1) Targeted PS combined with non-targeted broad spectrum antimicrobials;SA2) Targeted PS combined with targeted triggered release of two types of broad spectrum antimicrobials and SA3) Targeted PS combined with an antimicrobial peptide. The strength of our research team lies in the combined expertise of two centers: the Center for BioInspired Nanomaterials and the Center for Biofilm Engineering. We have specifically designed the experiments so that the most promising systems can be tested in an animal model of periodontal disease. PUBLIC HEALTH RELEVANCE: The bone loss and tissue destruction that accompany periodontal disease are caused by the response of the immune system to bacteria. However, we know that the immune system can live in harmony with many types of bacteria. Our research will provide a tool to selectively eliminate bacteria suspected of causing immune malfunction while sparing bacteria thought to be beneficial.